CN109761845A - A kind of synthetic method of N-nitroso-4-aminobutyrate compound - Google Patents
A kind of synthetic method of N-nitroso-4-aminobutyrate compound Download PDFInfo
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- CN109761845A CN109761845A CN201910130353.6A CN201910130353A CN109761845A CN 109761845 A CN109761845 A CN 109761845A CN 201910130353 A CN201910130353 A CN 201910130353A CN 109761845 A CN109761845 A CN 109761845A
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- -1 N-nitroso-4-aminobutyrate compound Chemical class 0.000 title claims abstract description 20
- 238000010189 synthetic method Methods 0.000 title claims description 9
- 238000000034 method Methods 0.000 claims abstract description 27
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 30
- 235000019441 ethanol Nutrition 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 230000001476 alcoholic effect Effects 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 7
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- NLJAGSJEAGPLOW-RUZDIDTESA-N C([C@@H](NC(=O)C(C)(N)C)C(=O)N1CCC(CC1)C=1C(=CC=CC=1)CCC1=NNN=N1)CCC1=CC=CC=C1 Chemical compound C([C@@H](NC(=O)C(C)(N)C)C(=O)N1CCC(CC1)C=1C(=CC=CC=1)CCC1=NNN=N1)CCC1=CC=CC=C1 NLJAGSJEAGPLOW-RUZDIDTESA-N 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 63
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 239000011734 sodium Substances 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 238000010791 quenching Methods 0.000 description 19
- 230000000171 quenching effect Effects 0.000 description 19
- 238000000926 separation method Methods 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 239000012263 liquid product Substances 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 13
- 229910052708 sodium Inorganic materials 0.000 description 13
- 238000005660 chlorination reaction Methods 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000007034 nitrosation reaction Methods 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- KVTNUOLCPOYLGY-UHFFFAOYSA-N 4-(2-oxohydrazinyl)butanoic acid Chemical class N(=O)NCCCC(=O)O KVTNUOLCPOYLGY-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 150000001804 chlorine Chemical class 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- BITRJENGLFIDFO-UHFFFAOYSA-N CCOC(=O)CCCN(C1=CC=CC=C1)N=O Chemical compound CCOC(=O)CCCN(C1=CC=CC=C1)N=O BITRJENGLFIDFO-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明公开了一种N‑亚硝基‑4‑氨基丁酸酯类化合物的合成方法，属于酯类化合物的合成技术领域。本发明的技术方案要点为：本发明与现有技术相比具有以下优点：(1)合成过程为一锅串联反应，操作简便，效率高；(2)原料易于得到；(3)反应在60℃以下进行，条件温和，操作简便；(4)底物的适用范围广。The invention discloses a method for synthesizing N-nitroso-4-aminobutyric acid ester compounds, and belongs to the technical field of synthesis of ester compounds. The main points of the technical solution of the present invention are: Compared with the prior art, the present invention has the following advantages: (1) the synthesis process is a one-pot series reaction, the operation is simple and the efficiency is high; (2) the raw materials are easy to obtain; (3) the reaction is carried out below 60 DEG C, the conditions are mild, and the operation It is simple and convenient; (4) the substrate has a wide range of applications.
Description
Technical field
The invention belongs to the synthesis technical fields of ester type compound, and in particular to a kind of N- nitroso -4-Aminobutanoicacid ester
The synthetic method of class compound.
Background technique
N- nitroso -4-Aminobutanoicacid ester type compound includes nitroso and the ester functional groups of high reaction activity simultaneously,
It is widely used in as important organic synthesis intermediate in fields such as bio-pharmaceuticals, pesticide and industrial dyes.
Currently, the synthetic method of such compound mainly has: 1) nucleophilic displacement of fluorine-nitrosation reaction of primary amine and bromobutyric acid ester；2) it takes
For Michael's addition-decarboxylation-nitrosation reaction of glycine and acrylate；3) pair of primary amine and 4- chlorobutyroyl chloride and alcohol
Nucleophilic displacement of fluorine-nitrosation reaction etc..Although these methods can effectively synthesize N- nitroso -4-Aminobutanoicacid esters chemical combination
Object, but there are still some urgent problems, such as: reaction raw materials are difficult to obtain, severe reaction conditions and synthesis step
Cumbersome etc., these shortcomings are but also the practicability of the above method is very limited.In view of this, further studying and opening
Hair synthesizes simple and direct, the efficient new method of N- nitroso -4-Aminobutanoicacid ester type compound with important from the raw material being easy to get
Theory significance and application value.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of synthesis sides of N- nitroso -4-Aminobutanoicacid ester type compound
Method, this method directly obtain N- nitroso -4-Aminobutanoicacid ester from the raw material simply easily prepared, by one pot of tandem reaction
Class compound has many advantages, such as easy to operate, mild condition and wide application range of substrates, is suitable for industrialized production.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of N- nitroso -4-Aminobutanoicacid esters
The synthetic method of compound, it is characterised in that detailed process are as follows: N- aryl substituted piperidines 1 are dissolved in alcoholic solvent,
Then be added oxidant and nitrite tert-butyl (tBuONO, TBN), it is reacted in 25-60 DEG C N- nitrous is made in air atmosphere
Base -4-Aminobutanoicacid ester type compound 2, the reaction equation in synthesis process are as follows:
Wherein R1For phenyl or substituted-phenyl, the substituent group on the substituted-phenyl phenyl ring is fluorine, chlorine, bromine, trifluoromethyl, cyanogen
Base, methyl or phenyl, R2For hydrogen, methyl or phenyl, 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate of oxidant or
2,2,6,6- tetramethyl -1- oxyl perchlorate, alcoholic solvent C1-5Alkylol.
Further preferably, the alcoholic solvent is methanol, ethyl alcohol, butanol, isobutanol or isopropanol.
Further preferably, the substance that feeds intake of the N- aryl substituted piperidines 1, nitrite tert-butyl and oxidant
The ratio between amount be 1:2-4:1.5-2.
Further preferably, the charge ratio of the N- aryl substituted piperidines 1 and alcoholic solvent is 0.2mmol:
1mL。
Compared with the prior art, the present invention has the following advantages: (1) synthesis process be one pot tandem reaction, easy to operate,
It is high-efficient；(2) raw material is readily available；(3) reaction is carried out at 60 DEG C or less, and mild condition is easy to operate；(4) substrate is applicable
Range is wide.Therefore, the present invention provides a kind of economic and practical for the synthesis of N- nitroso -4-Aminobutanoicacid ester type compound
New method.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
Compound 1a (0.2mmol, 32mg) and ethyl alcohol (C are added in the reaction flask of 15mL2H5OH, 1mL), then it is added
2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T+BF4 -, 0.3mmol, 73mg) and TBN (90wt%, 0.6mmol,
79μL).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL saturated sodium chloride solution quenching reaction is then added, uses second
Acetoacetic ester extracts (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake silica gel post separation (petroleum ether/
Ethyl acetate=20:1, v/v) obtain yellow liquid product N- nitroso-N- phenyl -4-Aminobutanoicacid ethyl ester 2a (30mg, 64%).
The characterize data of the compound is as follows:1H NMR(600MHz,CDCl3)δ:1.17-1.20(m,3H),1.80-1.83(m,2H),
2.25 (t, J=7.2Hz, 2H), 4.01-4.08 (m, 4H), 7.28-7.31 (m, 1H), 7.40-7.43 (m, 2H), 7.51-7.53
(m,2H).13C NMR(100MHz,CDCl3)δ:14.2,21.7,31.3,42.8,60.7,119.3,127.4,129.6,
141.5,172.6.MS:m/z 259[M+Na]+。
Embodiment 2
Compound 1a (0.2mmol, 32mg) and ethyl alcohol (C are added in the reaction flask of 15mL2H5OH, 1mL), then it is added
2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T+BF4 -, 0.4mmol, 97mg) and TBN (90wt%, 0.6mmol,
79μL).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL saturated sodium chloride solution quenching reaction is then added, uses second
Acetoacetic ester extracts (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake silica gel post separation (petroleum ether/
Ethyl acetate=20:1, v/v) obtain yellow liquid product 2a (25mg, 53%).
Embodiment 3
Compound 1a (0.2mmol, 32mg) and ethyl alcohol (C are added in the reaction flask of 15mL2H5OH, 1mL), then it is added
2,2,6,6- tetramethyl -1- oxyl perchlorate (T+ClO4 -, 0.3mmol, 77mg) and TBN (90wt%, 0.6mmol, 79
μL).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL saturated sodium chloride solution quenching reaction is then added, uses acetic acid
Ethyl ester extracts (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, and crosses silica gel post separation (petroleum ether/second
Acetoacetic ester=20:1, v/v) obtain yellow liquid product 2a (20mg, 42%).
Embodiment 4
Compound 1a (0.2mmol, 32mg) and ethyl alcohol (C are added in the reaction flask of 15mL2H5OH, 1mL), then it is added
2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T+BF4 -, 0.3mmol, 73mg) and TBN (90wt%, 0.4mmol,
53μL).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL saturated sodium chloride solution quenching reaction is then added, uses second
Acetoacetic ester extracts (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake silica gel post separation (petroleum ether/
Ethyl acetate=20:1, v/v) obtain yellow liquid product 2a (21mg, 44%).
Embodiment 5
Compound 1a (0.2mmol, 32mg) and ethyl alcohol (C are added in the reaction flask of 15mL2H5OH, 1mL), then it is added
2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T+BF4 -, 0.3mmol, 73mg) and TBN (90wt%, 0.8mmol,
105μL).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL saturated sodium chloride solution quenching reaction is then added, uses
Ethyl acetate extracts (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, and crosses silica gel post separation (petroleum
Ether/ethyl acetate=20:1, v/v) obtain yellow liquid product 2a (28mg, 59%).
Embodiment 6
Compound 1a (0.2mmol, 32mg) and ethyl alcohol (C are added in the reaction flask of 15mL2H5OH, 1mL), then it is added
2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T+BF4 -, 0.3mmol, 73mg) and TBN (90wt%, 0.6mmol,
79μL).It is stirred to react in air atmosphere in 60 DEG C 6 hours, 10mL saturated sodium chloride solution quenching reaction is then added, uses second
Acetoacetic ester extracts (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake silica gel post separation (petroleum ether/
Ethyl acetate=20:1, v/v) obtain yellow liquid product 2a (25mg, 53%).
Embodiment 7
By method described in embodiment 1, compound 1b (0.2mmol, 36mg) and ethyl alcohol are added in the reaction flask of 15mL
(C2H5OH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2b (31mg, 61%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 1.24-1.28 (m, 3H), 1.84-1.88 (m, 2H), 2.32 (t, J=
7.2Hz, 2H), 4.05-4.08 (m, 2H), 4.14 (q, J=7.2Hz, 2H), 7.16-7.20 (m, 2H), 7.55-7.58 (m,
2H).13C NMR(150MHz,CDCl3)δ:14.2,21.6,31.1,43.2,60.7,116.5(d,2JC-F=23.1Hz),
121.3(d,3JC-F=8.7Hz), 137.7 (d,4JC-F=3.2Hz), 161.8 (d,1JC-F=246.2Hz), 172.6.19F NMR
(376MHz,CDCl3)δ:-114.6.MS:m/z 277[M+Na]+。
Embodiment 8
By method described in embodiment 1, compound 1c (0.2mmol, 39mg) and ethyl alcohol are added in the reaction flask of 15mL
(C2H5OH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2c (44mg, 82%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 1.17-1.21 (m, 3H), 1.76-1.81 (m, 2H), 2.25 (t, J=
6.8Hz, 2H), 3.97-4.01 (m, 2H), 4.07 (q, J=7.2Hz, 2H), 7.37-7.40 (m, 2H), 7.47-7.50 (m,
2H).13C NMR(150MHz,CDCl3)δ:14.2,21.5,31.1,42.6,60.7,120.2,129.7,132.9,140.0,
172.5.MS:m/z 293[M+Na]+。
Embodiment 9
By method described in embodiment 1, compound 1d (0.2mmol, 48mg) and ethyl alcohol are added in the reaction flask of 15mL
(C2H5OH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2d (52mg, 83%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 1.17-1.21 (m, 3H), 1.76-1.81 (m, 2H), 2.24 (t, J=
6.8Hz, 2H), 3.97-4.00 (m, 2H), 4.07 (q, J=6.8Hz, 2H), 7.42-7.45 (m, 2H), 7.52-7.55 (m,
2H).13C NMR(150MHz,CDCl3)δ:14.2,21.5,31.1,42.5,60.7,120.4,120.7,132.7,140.5,
172.5.MS:m/z 337[M+Na]+。
Embodiment 10
By method described in embodiment 1, compound 1e (0.2mmol, 46mg) and ethyl alcohol are added in the reaction flask of 15mL
(C2H5OH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2e (19mg, 31%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 1.27 (t, J=7.2Hz, 3H), 1.84-1.90 (m, 2H), 2.34 (t, J
=6.8Hz, 2H), 4.08-4.18 (m, 4H), 7.74-7.80 (m, 4H)13C NMR(100MHz,CDCl3)δ:14.2,21.4,
31.0,42.1,60.8,118.3,123.9(q,1JC-F=270.1Hz), 126.9 (q,4JC-F=3.7Hz), 128.6 (q,2JC-F
=28.9Hz), 144.2,172.5.19F NMR(376MHz,CDCl3)δ:-62.5.MS:m/z 327[M+Na]+。
Embodiment 11
By method described in embodiment 1, compound 1f (0.2mmol, 37mg) and ethyl alcohol are added in the reaction flask of 15mL
(C2H5OH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2f (19mg, 36%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 1.28 (t, J=7.2Hz, 3H), 1.82-1.87 (m, 2H), 2.35 (t, J
=6.8Hz, 2H), 4.06-4.10 (m, 2H), 4.16 (q, J=7.2Hz, 2H), 7.77-7.83 (m, 4H)13C NMR
(100MHz,CDCl3)δ:14.2,21.3,30.9,41.7,60.8,110.3,118.1,118.3,133.7,144.8,
172.5.MS:m/z 284[M+Na]+。
Embodiment 12
By method described in embodiment 1, compound 1g (0.2mmol, 35mg) and ethyl alcohol are added in the reaction flask of 15mL
(C2H5OH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2g (15mg, 30%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 1.24-1.27 (m, 3H), 1.85-1.89 (m, 2H), 2.31 (t, J=
6.8Hz,2H),2.40(s,3H),4.06-4.16(m,4H),7.26-7.29(m,2H),7.46(dd,J1=6.8Hz, J2=
2.0Hz,2H).13C NMR(100MHz,CDCl3)δ:14.2,21.0,21.7,31.3,43.0,60.7,119.5,130.1,
137.4,139.0,172.6.MS:m/z 273[M+Na]+。
Embodiment 13
By method described in embodiment 1, compound 1h (0.2mmol, 47mg) and ethyl alcohol are added in the reaction flask of 15mL
(C2H5OH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2h (36mg, 58%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 1.24-1.28 (m, 3H), 1.87-1.95 (m, 2H), 2.34 (t, J=
7.2Hz,2H),4.11-4.18(m,4H),7.36-7.40(m,1H),7.45-7.49(m,2H),7.61-7.63(m,2H),
7.66-7.72(m,4H).13C NMR(150MHz,CDCl3)δ:14.2,21.7,31.3,42.7,60.7,119.4,127.0,
127.7,128.2,129.0,139.9,140.3,140.6,172.6.MS:m/z 335[M+Na]+。
Embodiment 14
By method described in embodiment 1, compound 1i (0.2mmol, 42mg) and ethyl alcohol are added in the reaction flask of 15mL
(C2H5OH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2i (36mg, 63%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 1.21 (d, J=7.2Hz, 3H), 1.25-1.30 (m, 3H), 1.63-1.67
(m,1H),1.85-1.88(m,1H),2.41-2.47(m,1H),3.87-3.94(m,1H),4.11-4.20(m,3H),7.32-
7.34 (m, 1H), 7.41 (t, J=7.6Hz, 1H), 7.47-7.50 (m, 1H), 7.63 (t, J=2.0Hz, 1H)13C NMR
(150MHz,CDCl3)δ:14.2,17.4,29.7,37.3,41.6,60.7,116.8,119.1,127.1,130.6,135.4,
142.6,175.5.MS:m/z 307[M+Na]+。
Embodiment 15
By method described in embodiment 1, compound 1j (0.2mmol, 47mg) and ethyl alcohol are added in the reaction flask of 15mL
(C2H5OH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow solid product 2j (32mg, 51%).The table of the compound
It is as follows to levy data: mp 50-51 DEG C1H NMR(400MHz,CDCl3) δ: 1.20 (t, J=7.2Hz, 3H), 1.98-2.05 (m,
1H),2.26-2.35(m,1H),3.51-3.55(m,1H),3.87-3.95(m,1H),4.06-4.18(m,3H),7.00-7.37
(m,6H),7.43-7.52(m,4H).13C NMR(150MHz,CDCl3)δ:14.1,29.8,42.0,49.2,61.1,119.3,
127.4,127.7,127.8,128.9,129.6,138.0,141.4,173.0.MS:m/z 335[M+Na]+。
Embodiment 16
By method described in embodiment 1, compound 1a (0.2mmol, 32mg) and methanol are added in the reaction flask of 15mL
2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added in (MeOH, 1mL)+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2k (11mg, 25%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 1.87-1.92 (m, 2H), 2.33 (t, J=7.2Hz, 2H), 3.68 (s,
3H),4.08-4.11(m,2H),7.35-7.39(m,1H),7.47-7.51(m,2H),7.58-7.60(m,2H).13C NMR
(150MHz,CDCl3)δ:21.7,31.0,42.7,51.8,119.3,127.4,129.6,141.4,173.0.MS:m/z 245
[M+Na]+。
Embodiment 17
By method described in embodiment 1, compound 1a (0.2mmol, 32mg) and butanol are added in the reaction flask of 15mL
(nBuOH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -, 0.3mmol, 73mg) and
TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, and anhydrous sodium sulfate is dry.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) obtains yellow liquid product 2l (27mg, 51%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ: 0.93 (t, J=7.2Hz, 3H), 1.25-1.40 (m, 2H), 1.57-1.64
(m, 2H), 1.84-1.92 (m, 2H), 2.32 (t, J=6.8Hz, 2H), 4.06-4.11 (m, 4H), 7.35-7.39 (m, 1H),
7.46-7.50(m,2H),7.58-7.61(m,2H).13C NMR(150MHz,CDCl3)δ:13.7,19.1,21.7,30.6,
31.3,42.8,64.6,119.3,127.4,129.6,141.5,172.7.MS:m/z 287[M+Na]+。
Embodiment 18
By method described in embodiment 1, compound 1a (0.2mmol, 32mg) and isobutyl are added in the reaction flask of 15mL
Alcohol (iBuOH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -,0.3mmol,73mg)
With TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorine
Change sodium solution quenching reaction, be extracted with ethyl acetate (10mL × 3), merge organic phase, anhydrous sodium sulfate is dry.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) and obtains yellow liquid product 2m (20mg, 38%).The compound
Characterize data is as follows:1H NMR(400MHz,CDCl3) δ: 0.91 (d, J=6.8Hz, 3H), 0.92 (d, J=6.8Hz, 3H),
1.85-1.94 (m, 3H), 2.34 (t, J=6.8Hz, 2H), 3.86 (d, J=6.8Hz, 2H), 4.08-4.12 (m, 2H), 7.35-
7.39(m,1H),7.48(td,J1=7.2Hz, J2=1.6Hz, 2H), 7.58-7.61 (m, 2H)13C NMR(150MHz,
CDCl3)δ:19.1,21.7,27.7,31.2,42.8,70.8,119.3,127.4,129.6,141.5,172.7.MS:m/z
287[M+Na]+。
Embodiment 19
By method described in embodiment 1, compound 1a (0.2mmol, 32mg) and isopropyl are added in the reaction flask of 15mL
Alcohol (iBuOH, 1mL), 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate (T are then added+BF4 -,0.3mmol,73mg)
With TBN (90wt%, 0.6mmol, 79 μ L).Reaction 6 hours is stirred at room temperature in air atmosphere, 10mL is then added and is saturated chlorine
Change sodium solution quenching reaction, be extracted with ethyl acetate (10mL × 3), merge organic phase, anhydrous sodium sulfate is dry.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1, v/v) and obtains yellow liquid product 2n (17mg, 34%).The compound
Characterize data is as follows:1H NMR(400MHz,CDCl3) δ: 1.23 (d, J=6.8Hz, 3H), 1.24 (d, J=7.2Hz, 3H),
1.84-1.91 (m, 2H), 2.29 (t, J=7.2Hz, 2H), 4.07-4.11 (m, 2H), 4.98-5.03 (m, 1H), 7.35-7.39
(m,1H),7.46-7.50(m,2H),7.58-7.61(m,2H).13C NMR(150MHz,CDCl3)δ:21.7,21.8,31.6,
42.9,68.1,119.3,127.4,129.6,141.5,172.1.MS:m/z 273[M+Na]+。
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (4)
1. a kind of synthetic method of N- nitroso -4-Aminobutanoicacid ester type compound, it is characterised in that detailed process are as follows: by N- virtue
Base substituted piperidines 1 are dissolved in alcoholic solvent, be then added oxidant and nitrite tert-butyl (tBuONO, TBN), in sky
It is reacted under gas atmosphere in 25-60 DEG C and N- nitroso -4-Aminobutanoicacid ester type compound 2 is made, the reactional equation in synthesis process
Formula are as follows:
Wherein R1For phenyl or substituted-phenyl, the substituent group on the substituted-phenyl phenyl ring is fluorine, chlorine, bromine, trifluoromethyl, cyano, first
Base or phenyl, R2For hydrogen, methyl or phenyl, 2,2,6,6- tetramethyl -1- oxyl tetrafluoroborate of oxidant or 2,2,
6,6- tetramethyl -1- oxyl perchlorate, alcoholic solvent C1-5Alkylol.
2. the synthetic method of N- nitroso -4-Aminobutanoicacid ester type compound according to claim 1, it is characterised in that:
The alcoholic solvent is methanol, ethyl alcohol, butanol, isobutanol or isopropanol.
3. the synthetic method of N- nitroso -4-Aminobutanoicacid ester type compound according to claim 1, it is characterised in that:
The ratio between amount for the substance that feeds intake of the N- aryl substituted piperidines 1, nitrite tert-butyl and oxidant is 1:2-4:
1.5-2。
4. the synthetic method of N- nitroso -4-Aminobutanoicacid ester type compound according to claim 1, it is characterised in that:
The charge ratio of the N- aryl substituted piperidines 1 and alcoholic solvent is 0.2mmol:1mL.
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| CN106631646A (en) * | 2016-08-26 | 2017-05-10 | 河南师范大学 | Synthetic method of (E)-4-oxo-2-butenal compound |
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| CN110483377A (en) * | 2019-09-12 | 2019-11-22 | 河南师范大学 | A kind of synthetic method of N- nitroso -2- alkane aminooxy group aldehyde compound |
| CN110483377B (en) * | 2019-09-12 | 2021-06-04 | 河南师范大学 | A kind of synthetic method of N-nitroso-2-alkane aminooxy aldehyde compound |
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